Friday, August 29
For the most up-to-date agenda, please download the full event guide
7:30 am Morning Check-In: Served with Coffee & Light Breakfast
7:55 am Chair’s Opening Remarks
REFINING PRECLINICAL STRATEGY & TRANSLATIONAL CONFIDENCE FOR CNS-DIRECTED OLIGONUCLEOTIDE THERAPEUTICS
8:00 am Advancing RNA Editing Therapeutics for Rett Syndrome: Targeting the Root Cause with CNS-Directed Oligonucleotides
Synopsis
- Introducing ProQR’s RNA editing platform and its potential to correct disease causing mutations in MECP2, the primary gene implicated in Rett Syndrome
- Highlighting preclinical data demonstrating targeted editing in the brain using CNS-delivery conjugates and oligonucleotide-based strategies
- Discuss the translational path, including biomarker strategies and candidate selection from non-human primate (NHP) studies, to inform clinical entry
- Outline the near-term development timeline with clinical candidate nominations expected this year and next, and reflect on parallel efforts in liver-directed RNA editing
8:30 am Rational ASO Design in CNS Disorders: Cell-Type Targeting & Functional Validation in Complex BBBoid In Vitro Systems
Synopsis
- Design antisense oligonucleotides against genetically defined mutations in diseases like Alzheimer’s, ALS, and autism offers a powerful advantage when using in vitro models that accurately reflect the human genetic background
- Discuss the importance of assessing the functional consequences of target modulation, leveraging multiplexed molecular and phenotypic readouts to understand downstream effects in disease-relevant pathways
- Iterative optimization of ASO chemistry, dosing, and delivery enables enhanced cell-type specificity, which is critical when working without access to human in vivo systems
- Develop and tailor platform technologies that can adapt to disease-specific needs is key to building biomimetic in vitro systems with translational relevance across neurodegenerative and neuropsychiatric disorders
9:00 am Harnessing a Large Animal Model to Overcome Translational Barriers in Angelman Syndrome
Synopsis
- Unpack why mouse models fail to recapitulate Angelman syndrome phenotypes and challenges associated with rodent models in preclinical development
- Rationale and characterization of the Angelman pig model, including phenotypic fidelity, regulatory implications, and translational value
- Target discovery in a complex genomic landscape: Exploring how integrated approaches in genetics and biology helped identify functionally relevant regions for therapeutic development for Angelman syndrome
9:30 am Morning Break & Refreshments
DERISKING OLIGONUCLEOTIDE TOX PROFILES TO ENHANCE THERAPEUTIC WINDOW & BRIDGE THE TRANSLATIONAL GAP
10:30 am Translating ASO Findings to the Clinic to Transform Outcomes in Neurodevelopmental Diseases
Synopsis
- Unveil ASO preclinical data and NHP tox package
- Share first in human clinical data from ASO neurodevelopmental data
11:00 am Advancing a Splice-Modulating ASO Restoring UNC13A protein for ALS: Nonclinical Studies Guided Optimization of the Clinical Trial Design
Synopsis
- Presenting pharmacology and PK strategies to support clinical trials with a splice-modulating ASO designed to correct UNC13A mis-splicing associated with TDP-43 pathology in ALS
- How regulatory feedback shaped the nonclinical strategy and the clinical trial design
- Early learnings from IND-enabling studies and the path toward initiating first-in-human trials within the year
- Optimizing clinical trial design and dosing strategy to balance therapeutic impact with risks of overaccumulation in the CNS
11:30 am Roundtable Discussion: Demonstrating Reduced Chronic Oligonucleotide Toxicity Across Both Rodents & NHP Models
Synopsis
- Accumulate chronic toxicity data in NHPs to understand common threads in toxicities and understand the pathology underlying chronic toxicity
- Build cutting edge rodent models that can recapitulate chronic oligonucleotide toxicity by reverse translating observations in NHPs, overcoming the disconnect in toxicity observations between NHPs and rodent systems with oligonucleotides
- Integrate models into clinical practice to more robustly determine candidate safety before reaching clinical trials
12:00 pm Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics
Synopsis
- Considerations for new chemistries and indications for oligos, as well as considerations for common, rare and ultra-rare indications
- The FDAs views regarding platforms and platform technology
- Evaluate what kind of safety data needs to be shown to demonstrate safety
- Map out differences in regulatory requirements between US, Europe and more
12:30 pm Lunch & Networking Break
REFINING OLIGONUCLEOTIDE DESIGN TO ENSURE SUFFICIENT PENETRATION TO THE DEEP BRAIN TO TREAT DIVERSE DISEASES
1:30 pm Roundtable Discussion: Advancing Dose Selection & Translational PK/PD Modeling for Oligonucleotide Therapeutics & Brain Shuttles in the CNS
Synopsis
- Leverage translational PK/PD modeling to inform dose selection and understand exposure-response relationships in the CNS for oligonucleotide-based therapies
- Explore brain shuttle and Transferrin Receptor mediated uptake and modeling strategies to assess CNS exposure and PK ‘hit’
- Integrate intrathecal distribution data into predictive frameworks to optimize therapeutic delivery and biodistribution
- Case examples and lessons learned from neuroscience and oligonucleotide programs to support clinical translation and decision making
2:00 pm Leveraging Computational Modeling for Precision Intra CSF Delivery in the CNS with FalconTM
Synopsis
- Unpack FalconTM as a systematic approach for developing intra-CSF drugs including disease-specific understanding of CSF drug interactions, systematically optimizing drug dose, formulation and biodistribution to maximize translational success
- Utilize high resolution MRI for better resolution and generation of computer models for advanced capacity for testing over in vivo/in vitro analysis
- Simulate a multitude of delivery scenarios and extrapolating protocols across species, to mimic the patient condition at different disease states and reduce the reliance on extensive animal studies
- Explore regulatory acceptance of computational modeling to support proof of concept in IND
- Advance indications across SMA, ALS/FTD and other neurodegeneration and more
2:30 pm Afternoon Break & Refreshments
WHAT’S NEXT BEYOND TFR1 CONJUGATES? SPOTLIGHTING AN AERIAL VIEW OF AAV, SMALL MOLECULE, NANOPEPTIDE & APOE1 APPROACHES TO UNVEIL NEXT GENERATION BRAIN SHUTTLES IN NEUROLOGY
3:00 pm siRNA Brain Shuttle Strategies for Neurometabolic Modulation
Synopsis
- Overviewing neurometabolic axis and CS targets by targeting central regulators of hunger, satiety, and hedonic drive
- The impact of blood-brain barrier on distribution to different brain regions as compared to intrathecal injection as illustrated through ISH imaging analysis
3:30 pm Panel Discussion: Brain Shuttles Beyond TFR1: What Will Be the Next Hot Brain Shuttle?
Synopsis
- Evaluate the opportunities in overcoming target delivery challenges with TfR1 overexpression and off-target specificity
- Explore small molecules, APOE1 peptides, nanopeptides, carbohydrates, LNPs as alternative ligands comparing pros, cons and negatives; evaluating opportunities where different ligands might be more ‘fit-for-purpose’
4:00 pm Panel Discussion: The Future of Oligonucleotide Therapeutics: Where Will the Field Be in 5 Years?
Synopsis
- How will advances in conjugation strategies, nanoparticle formulations, and tissue-specific targeting improve oligonucleotide biodistribution and efficacy?
- Beyond ALS, Huntington’s Disease & Alzheimer’s. What new indications, such as neurogenetic, epilepsies, neurodevelopmental and neuropsychiatric, are emerging for oligonucleotide-based therapies?
- What hurdles remain in scaling oligonucleotide production, and how will evolving regulatory frameworks shape the clinical and commercial landscape?
- How will AI and ML accelerate oligonucleotide drug discovery, from sequence optimization to in silico toxicity prediction?